RU2359692C2 - Medicinal preparation for treatment of diseases of cardiocerebral blood vessels and way of its manufacturing - Google Patents

Abstract

FIELD: medicine, pharmaceutics. ^ SUBSTANCE: invention concerns a pharmaceutical industry, in particular to a medicinal preparation for treatment of cardiovascular and cerebrovascular diseases. A medicinal preparation for treatment of the cardiovascular and cerebrovascular diseases, containing iso lithis sperm acids A and B which are characterised in mass spectra by certain peaks. The way of manufacturing of a medicinal preparation including weighing of Radix Salviae Miltiorrhizae and Radix Notoginseng; addition of a hydroxide of sodium, Sodium hydrogenum, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate or their admixture in certain quantity; boiling of admixtures in 3-6-time quantity of water 2-4 times; filtration of an admixture and concentration of incorporated filtrates; addition of ethanol infusion of an admixture and separation of the supernatant liquid; allocation of ethanol from the supernatant liquid and concentration of the rest with reception of extract Radix Salviae Miltiorrhizae - Radix Notoginseng, mixing of the received extract with borneol or oil Lignum Dalbergie Odoriferae (rosewood); and excipient addition. ^ EFFECT: development of a preparation, effective for treatment of cardiovascular and cerebrovascular diseases. ^ 11 cl, 6 dwg, 7 tbl, 9 ex

Description

FIELD OF THE INVENTION

This invention relates to medicine and, in particular, to a traditional Chinese drug for the treatment of cardiovascular and cerebrovascular diseases.

BACKGROUND OF THE INVENTION

Cardiovascular and cerebrovascular diseases are common diseases that cause great harm to human health. Recently, such diseases are increasingly occurring due to changes in working conditions, life, nutrition, the environment, etc. with the development of society. Traditional Chinese medicine (TCM), despite its low activity in relation to one target in comparison with Western medicine, is characterized by multiple methods of application and targets, dynamic and holistic treatment and minor side effects and is significantly superior to Western medicine. The TCM drug with a specific therapeutic effect has a general therapeutic effect that is superior to the effect of Western medicine. Currently, there are many TCM drugs for the treatment of cardiovascular and cerebrovascular diseases, such as Danshen tablets and TCM based on it, drops and pills based on Guanxin Danshen, Xinkeshu tablets and others. These SCM drugs all containing Radix Salviae Miltiorrhizae (also known like danshen) and Radix Notoginseng, have different therapeutic effects due to different compositions, ratio of ingredients, extraction and purification methods or dosage forms. In addition, the quality of these preparations is difficult to control, since currently there are no effective qualitative methods to fully characterize the physical and chemical properties of these preparations, and complex biologically active ingredients in these preparations are characterized by only one or two compounds, such as Danshensu or Tanshinone IIA (Tanshinon IIA). Therefore, there is a need to improve the method of extraction and purification of such TCM preparations, as well as a method for controlling their quality.

SUMMARY OF THE INVENTION

The purpose of this invention is to create a more effective TCM preparation for the treatment of cardiovascular and cerebrovascular diseases. In addition, a method is provided that allows you to quite fully and accurately determine the physical and chemical characteristics of the drug.

Another objective of this invention is to provide a method for producing the above TCM preparation.

The objectives of this invention are achieved as follows.

The TCM preparation according to this invention can be obtained by a method comprising the following steps:

mixing Radix Salviae Miltiorrhizae (sage) and Radix Notoginseng (ginseng notoginseng) with sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate or a mixture thereof in an amount of 0.5 to 4% based on the total weight of these medicinal substances with obtaining a mixture;

boiling the mixture in 3-6-fold amount of water 2-4 times;

filtering the mixture and concentrating the combined filtrates;

adding ethanol with a high concentration (more than 70%) in an amount sufficient to obtain an ethanol content of 65-70%;

sedimentation of the mixture and separation of the supernatant;

separation of ethanol from the supernatant and concentration of the residue until its relative density becomes 1.20-1.50 (55-60 ° C) to obtain the Radix Salviae Miltiorrhizae extract - Radix Notoginseng;

mixing the resulting extract with borneol or Lignum Dalbergie oil

Odori ferae (fragrant dalbergia); and

the addition of one or more pharmacological excipients, such as starch, dextrin, lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, magnesium stearate, silicone microgel, xylitol, lactitol, glucose, glycine, mannitol, methylated starch sodium methyl starch, sodium methyl salt, crosslinked polyvinylpyrrolidone, etc., and the preparation of various dosage forms from this mixture, such as injection-molded tablets, sustained-release tablets, drip saws whether granules, powder for injection, capsules, microgranules, oral disintegrants. Preferably, the above TCM preparation is prepared by a process comprising the following steps:

weighing of Radix Salviae Miltiorrhizae and Radix Notoginseng;

the addition of sodium bicarbonate in an amount of 1.4-1.9% based on the total weight of the medicinal substances to obtain a mixture;

boiling the mixture in a 4-5-fold amount of water for 2-3 hours and then in a 3-4-fold amount of water for 1-2 hours;

filtering the mixture and concentrating the combined filtrates until a specific gravity of 1.16-1.20 (80 ± 5 ° C) is reached;

adding ethanol with a high concentration (above 70%) in an amount sufficient to obtain an ethanol content of 65-70% (20 ° C);

keeping the mixture for 8-12 hours and separating the supernatant;

the separation of ethanol from the supernatant and concentration of the residue to obtain a relative density of 1.32-1.40 (55-60 ° C) with the formation of the extract Radix Salviae Miltiorrhizae - Radix Notoginseng;

mixing said extract with borneol or Lignum Dalbergie Odoriferae oil; and

the addition of one or more pharmacological excipients selected from the group consisting of starch, dextrin, lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, magnesium stearate, silicone microgel, xylitol, lactitol, glucose, glycine, mannitol sodium chloride, sodium salt carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, etc., and the preparation of tablets, pills, injection powder, capsules, granules, micro granules or oral disintegrants from this mixture.

The borneol used may be natural or synthetic. The Lignum Dalbergie Odoriferae oil used in this invention is obtained by distillation of the Lignum Dalbergie Odoriferae.

The above TCM preparation is preferably prepared in the form of a dosage form of pills.

The TCM preparation of the present invention is characterized by the following physical and chemical parameters:

the chromatogram (HPLC) has 8 peaks, which are characterized by a ratio of the area of a single peak to the total peak area in excess of 2%; the average retention time for these 8 peaks is 6.04, 9.90, 16.89, 17.84, 20.31, 23.74, 27.73 and 31.02 respectively, and RSD% (standard deviation of retention time) is 0.31, 0.25, 0.61, 0.70, 0.96, 0.76, 0.50 and 1.18, respectively; the average peak area is 1627.92, 2575.54, 366.89, 381.40, 186.08, 555.35, 281.91 and 1852.33, respectively; and RSD% of the peak area is 5.91, 13.59, 10.92, 13.81, 12.04, 10.48, 18.08 and 14.84, respectively; and the ratio of the area of each individual peak to the total peak area is 19.6-22.0%, 28.5-37.4%, 4.2-5.2%, 4.2-5.5%, 2.1 -2.7%, 6.4-7.8%, 3.0-4.3% and 20.2-27.2%, respectively.

The indicated physical and chemical parameters were obtained under the following conditions.

(1) High Resolution Liquid Chromatography

Octadecylsilyl silica gel was used as a filler for the chromatographic column; the flow rate was 1,000 ml / min at a wavelength of 280 nm. Elution was carried out under the following conditions: the mobile phase A was a 0.02% aqueous solution of phosphoric acid, the mobile phase B was 80% acetonitrile - 0.02% aqueous solution of phosphoric acid; the mobile phase A changed uniformly from 90 to 78% and the mobile phase B changed uniformly from 10 to 22% for 0-8 minutes; mobile phase A changed from 78 to 74%, and mobile phase B from 22 to 26% for 8-15 minutes; mobile phase A changed from 74 to 48% and mobile phase B from 26 to 52% within 15-55 minutes.

(2) Preparation and analysis of sample solution

10 pills of the TCM preparation according to the invention were accurately weighed, then they were placed in a 10 ml vessel. Distilled water was added in an amount sufficient to dissolve the pills with shaking and ultrasound for 15 minutes. Then, to achieve a volume of 10 ml, distilled water was added again. The resulting solution was centrifuged or filtered to obtain a sample solution. 10 μl of a sample of the solution was injected into an HPLC column and then HPLC was performed to obtain HPLC spectra. By comparing with the standard sample and mass spectra, the above 8 peaks were identified with an average retention time of 6.04, 9.90, 16.89, 17.84, 20.31, 23.74, 27.73 and 31.02 which correspond to Danshensu, protocatechialdehyde, isolispermic acid A, isolispermic acid B, salvianolic acid D, rosmarinic acid, salvianolic acid B and salvianolic acid A, respectively (see Figure 1).

The composition of the TCM preparation according to the invention was determined using the HPLC-MS method. It contains Danshensu, protocatechialdehyde, isolite sperm acid A, isolite sperm acid B, salvianolic acid D, salvianolic acid E, rosmarinic acid, salvianolic acid B, salvianolic acid , tanshinon I, tansinon II, notoginsenoside R ₁ , ginsenoside Re, ginsenoside Rg 1, ginsenoside Rb 1, notoginsenoside R2, notoginsenoside R2-iso, ginsenoside Rg 2, ginsenoside Rh 1, ginsenoside Rh1-iso, gind Ginsenosi Rf-H-20, notoginsenoside R2-H20, ginsenoside Rg6 or F4, ginsenoside Rk3, ginsenoside (Rh4), ginsenoside 20 (R) -Rg3, ginsenoside 20 (S) -Rg3, ginsenoside (Rk1), ginsenoside (Rg5) etc.

1. Danshensu MB = 198 2. Protocatechialdehyde MB = 138 3. Salvianolic acid A MB = 494 4. Salvianolic acid B MB = 718 5. Salvianolic acid C MB = 492 6. Salvianolic acid D MB = 418 7. Salvianolic acid E MB = 718 8. Salvianolic acid G MB = 340 9. Isolithospermic acid A MB = 538 10. Isolithospermic acid B MB = 538 11. Rosmarinic acid MB = 360

Type A structure Ginsenoside R ₁ R ₂ Molecular Weight (MB) Ginsenoside Rb ₁ Glc-glc Glc-glc 1108 Ginsenoside Rd Glc-glc Glc 946 Ginsenoside Rg ₃ Glc-glc H 784 Ginsenoside F ₂ Glc Glc 784 Type B structure Ginsenoside R ₁ R ₂ R ₃ MB Ginsenoside Re N Glc O-glc-rham 946 Ginsenoside rf N N O-glc-glc 800 Ginsenoside Rg ₁ N Glc O-glc 800 Ginsenoside Rg ₂ N N O-glc-rham 784 Ginsenoside Rh ₁ N N O-glc 638 Notoginsenoside R ₂ N N O-glc-xyl 770 Notoginsenoside R ₁ N Glc O-glc-xyl 932 Ginsenoside F ₁ N Glc IT 638

Type C structure Ginsenoside R ₁ R ₂ MB Ginsenoside Rg ₅ Glc-glc- N 766 Ginsenoside Rh ₄ N Glc-o- 620 Ginsenoside F ₄ N Rham-glc-o- 766 Type D structure Ginsenoside R ₁ R ₂ MB Ginsenoside Rg ₆ N Rham-glc-o- 766 Ginsenoside Rk ₁ Glc-glc H 766 Ginsenoside Rk ₃ N Glc-o- 620 Glc = β-D-glucose
Rham = α-L-ramnose
Xyl = β-D-xylose

During the extraction process and during the analysis according to the invention, fingerprinting atlas was used in the TCM preparation to completely characterize the physical and chemical properties of Radix Salviae Miltiorrhizae and Radix Notoginseng. Compared with the prior art, when complex biologically active ingredients in TCM preparations are characterized by only one or two compounds, this method is much more suitable for quality control of TCM preparations.

Biologically active ingredients in the TCM preparations of the invention were detected by HPLC-MS. As a result, 12 components were identified in Radix Salviae Miltiorrhizae and 21 components in Radix Notoginseng. Compounds were identified mainly by analysis of MS ⁿ data when comparing these data with literature. Finally, the structure of a large number of components was fully confirmed by comparison with control samples. It can be concluded that the method of analyzing the chemical composition of the TCM preparation according to the invention using HPLC-MS makes it possible to obtain extensive information about the structure of biologically active ingredients. The characterization of the physical and chemical properties of Radix Salviae Miltiorrhizae and Radix Notoginseng in the TCM preparation of the invention using this information is much more complete than using known methods.

The following experiments show that the TCM preparation according to the invention is effective for the treatment of cardiovascular and cerebrovascular diseases.

     1. The effect of TCM on myocardial ischemia and myocardial infarction in an anesthetized dog.

An epicardial electrogram was used to characterize myocardial ischemia and the degree of its development. To determine the area of myocardial infarction, quantitative histology was used (N-BT staining method). Changes in the flow of blood in the coronary artery, oxygen uptake by the myocardium and the activity of SK and LDH in serum and ET, TXB ₂ and 6-keto-PGF _1a in blood plasma were also determined. The effect of the TCM preparation according to the invention was studied with its alimentary administration in relation to its effect on myocardial ischemia, myocardial infarction and related indicators in the tested dogs.

The test results show that the TCM preparation of the invention has a significant effect on attenuating acute myocardial ischemia and myocardial infarction in dogs. This can lead to a decrease in ischemia (Σ-ST) shown on the epicardial electrogram (P <0.001 relative to the control group receiving physiological saline), to a significant decrease in the area of myocardial infarction, as evidenced by the N-ST staining method (P <0.01 relative to control group receiving saline) and a significant increase in blood flow in the coronary artery in the ischemic heart (P <0.001 relative to the control group receiving saline). The drug inhibits the release of serum lactate dehydrogenase (LDH) arising from coronary disease and myocardial infarction (the ratio of the relative change is significantly lower than the corresponding value in the control group receiving physiological saline P <0.001), as well as an increase in creatine phosphokinase (SC) activity ( the value of the relative change in the ratio is significantly lower than the corresponding value in the control group receiving saline solution P <0.05). The drug also affects the ET value in the blood plasma, decreasing it (P <0.001 relative to the control group receiving physiological saline), and the level of TXB ₂ (P <0.001 relative to the control group receiving physiological saline, P <0.05 in the group receiving TCM preparation) in plasma and improves the ratio of 6-keto-PGF _1a / TXB ₂ (P <0.001 relative to the control group receiving physiological saline, P <0.05 in the group receiving TCM preparation).

     2. The effect of TCM on myocardial infarction caused by ischemic reperfusion.

When observing a rat model with myocardial damage caused by reperfusion, it was found that the TCM preparation according to the invention can significantly reduce myocardial damage, the magnitude of the area of myocardial infarction (p <0.05-0.01 relative to the model group) and lead to less weight affected by a heart attack (p <0.05 relative to the model group). The drug also significantly increased the activity of superoxide dismutase (SOD) (p <0.01 relative to the model group).

     3. The effect of the TCM preparation on the dynamics of the blood flow and oxygen uptake by the myocardium in dogs.

The TCM preparation according to the invention was evaluated in relation to its effect on the dynamics of blood flow in the heart and myocardial oxygen absorption in anesthetized dogs.

The results show that the TCM preparation according to the invention can lead to significantly accelerated blood flow in the coronary artery (p <0.01-0.001 in the group prior to administration of the drug and the control group receiving physiological saline), an enlarged coronary vessel, and an increased oxygen content in the coronary coronary artery sinus (p <0.05-0.001 in the group before administration of the drug and the control group receiving physiological saline), a decreased indicator of oxygen absorption by the myocardium, an increase in the supply of blood to the heart muscle and by oxygen and to an increased volume per heartbeat and minute cardiac output (p <0.05-0.01 in the group prior to administration of the drug and the control group receiving saline) without accelerating the work of the left ventricle.

The TCM preparation according to the invention regulates the functioning of the heart and, thus, helps to adapt and improve the functioning of the cardiovascular system.

     4. The effect of TCM on platelet agglutination in rabbits.

The TCM preparation of the invention was evaluated using Born nephelometry with respect to its effect on platelet agglutination in rabbits.

The results show that TCM, when administered intragastrically for 7 consecutive days, leads to a significant decrease in platelet agglutination in rabbits caused by arachidonic acid (AA) (p <0.05-0.01 relative to the control group treated with distilled water) and collagen (p <0.01 relative to the control group receiving distilled water). This shows that the TCM preparation of the invention has an inhibitory effect on platelet agglutination.

     5. The effect of the TCM preparation on in vitro thrombogenesis and blood viscosity in rats.

The TCM preparation of the invention was evaluated for its effect on in vitro thrombogenesis and blood viscosity in rats.

The results show that the TCM preparation after intragastric administration for 7 consecutive days leads to a significantly lower thrombus (p <0.01 relative to the control group receiving distilled water), a decrease in the wet and dry weight of the thrombus (p <0.05 relative to the control group, treated with distilled water), to a reduced viscosity of blood plasma (p <0.001 relative to the control group receiving distilled water) and a reduced viscosity of all blood at different shear rates (p <0.05 relative to the control group, oluchavshey distilled water). This shows that the TCM preparation according to the invention is able to inhibit thrombogenesis and reduces the viscosity of blood plasma and all blood.

     6. The effect of TCM on hyperlipidemia and atherosclerosis in rabbits.

A model for the study of hyperlipidemia and atherosclerosis (AS) was obtained by feeding a rabbit high-cholesterol food. The TCM preparation of the invention was evaluated by its effect on this model.

The results show that the TCM preparation according to the invention leads to significantly lower serum concentrations of TC, TG, LDL-C, VLDL-C and a reduced TC / HDL-C ratio (p <0.05-0.001 relative to the control group suffering from hyperlipidemia ) in rabbits, to a significantly increased concentration of HDL-C (p <0.05 relative to the control group suffering from hyperlipidemia), to a reduced TS content in the aorta (p <0.05 relative to the control group suffering from hyperlipidemia), to a reduced content TG in the liver (p <0.05 relative to the control group, s Radaev from Hyperlipidemia), and a decreased content of MDA in the liver (p <0.001 relative to the control group suffering from Hyperlipidemia). The TCM preparation according to the invention significantly exceeds the activity of SOD in the liver (p <0.01 relative to the control group suffering from hyperlipidemia).

In addition, it significantly reduces the thickness of the aortic platelets and the number of foamed cells formed in the aorta (p <0.05 relative to the control group suffering from hyperlipidemia). It also leads to a decrease in platelet area in the aorta. This indicates that the TCM preparation according to the invention regulates the blood fat content and at the same time exerts a certain effect on the lipid anti-oxidation and the prevention of arteriosclerosis.

     7. The effect of TCM on localized cerebral ischemia in rats.

The TCM preparation of the invention was evaluated with respect to its effect on the cerebral infarction area in rats of the IRU using a rat model with moderate cerebral artery thrombosis (IRU).

The results show that the TCM preparation of the invention acts on anti-cerebral ischemia.

Brief Description of the Figures

     Figure 1 presents an atlas of fingerprints of the components of Radix Salviae Miltiorrhizae in pills, which are one of the dosage forms of the TCM preparation according to the invention. In this Figure, peak 1 corresponds to Danshensu; peak 2 represents protocachialdehyde, peak 3 represents isolispermic acid A, peak 4 corresponds to isolispermic acid B, peak 5 corresponds to salvianolic acid D, peak 6 corresponds to rosmarinic acid, peak 7 corresponds to salvianolic acid B and peak 8 to salvianolic acid A.

     Figure 2 shows the HPLC spectrum of the water-soluble components of Radix Salviae Miltiorrhizae in the TCM preparation of the invention. In this Figure, peak 1 corresponds to Danshensu; peak 2 represents protocachialdehyde, peak 3 represents isolispermic acid A, peak 4 corresponds to isolispermic acid B, peak 5 corresponds to salvianolic acid D, peak 6 corresponds to salvianolic acid E, peak 7 represents rosmarinic acid, peak 8 corresponds to salvianolic acid B, peak 9 corresponds to salvianolic acid G and peak 10 corresponds to salvianolic acid A.

     Figure 3 presents the MS-TIC spectrum of the water-soluble components of Radix Salviae Miltiorrhizae in the TCM preparation of the invention.

     Figure 4 shows the HPLC spectrum of the liposoluble components of Radix Salviae Miltiorrhizae in the TCM preparation of the invention. In this Figure, peak 1 corresponds to tachinon I, and peak 2 corresponds to tachinon IIA.

     Figure 5 presents the MS-TIC spectrum of the liposoluble components of Radix Salviae Miltiorrhizae in the TCM preparation of the invention.

     Figure 6 presents the MS-TIC spectrum of the components and Radix Notoginseng according to the invention.

Detailed Description of Embodiments

The invention will now be described in detail with reference to the following examples. These examples serve to illustrate and not limit the scope of the invention.

Examples

     Example 1 (preparative example)

41.06 g of Radix Salviae Miltiorrhizae and 8.03 g of Radix Notoginseng were weighed, to this mixture was added sodium bicarbonate in an amount of 1.8% of the total weight of these medicinal substances. The resulting mixture was boiled in a 4-fold amount of water for 2 hours and then in a 3-fold amount of water for another 1 hour. After filtration, the combined filtrates were concentrated to obtain a specific gravity of 1.19-1.20 (75 ± 1 ° С) . Then 95% ethanol was added in an amount sufficient to obtain an ethanol content of 65% (20 ° C). The mixture was then held for 12 hours and the supernatant was separated. Ethanol was isolated from the supernatant, and the residue was concentrated until a relative density of 1.37 (55-60 ° C) was obtained, and Radix Salviae Miltiorrhizae - Radix Notoginseng extract was obtained.

This extract was uniformly mixed with 0.46 g of borneol and 18 g of polyethylene glycol-6000. The mixture was melted at a temperature of 85 ° C for 80 minutes. Then the molten liquid was introduced into the receiver of the machine for the manufacture of droplet pills, and the temperature in the receiver was maintained equal to 86 ° C, in the machine, the liquid dropped into liquid paraffin at 8 ° C. The resulting “drop pills” were taken out, oil was removed from them and then sieved through a sieve to obtain the desired preparation.

     Example 2 (preparative example)

59.36 g of Radix Salviae Miltiorrhizae and 6.38 g of Radix Notoginseng were weighed, to this mixture was added potassium bicarbonate in an amount of 1.0% based on the total weight of these medicinal substances. The resulting mixture was boiled in a 4-fold amount of water for 2.5 hours and then in a 3-fold amount of water for another 1.5 hours. After filtration, the combined filtrates were concentrated to obtain a specific gravity of 1.19-1.20 (75 ± 1 ° C). Then, 85% ethanol was added in an amount providing an ethanol content of 70% (20 ° C). Then the mixture was kept for 10 h and the supernatant was separated. Ethanol was isolated from the supernatant, and the residue was concentrated until a relative density of 1.35 (55-60 ° C) was obtained, and Radix Salviae Miltiorrhizae - Radix Notoginseng extract was obtained.

This extract was uniformly mixed with 0.34 g of borneol and 23 g of polyethylene glycol-6000. The resulting mixture was melted at 89 ° C for 100 minutes. Then the melt was introduced into the receiver of the machine for the manufacture of droplet pills, and the receiver was maintained at a temperature of 85 ° C, the liquid was dripped into methyl silicone oil with a temperature of 8 ° C. The resulting “drop pills” were taken out, oil was removed from them and then sieved through a sieve to obtain the desired preparation.

     Example 3 (preparative example)

12.6 g of Radix Salviae Miltiorrhizae and 56.15 g of Radix Notoginseng were weighed, and potassium bicarbonate was added in an amount of 1.0% based on the total weight of these medicinal substances. The resulting mixture was boiled in a 4-fold amount of water for 2.5 hours and then in a 3-fold amount of water for another 1.5 hours. After filtration, the combined filtrates were concentrated to obtain a specific gravity of 1.19-1.20 (75 ± 1 ° C). Then 95% ethanol was added in an amount sufficient to obtain an ethanol content of 70% (20 ° C). Then the mixture was kept for 10 h and the supernatant was separated. Ethanol was separated from the supernatant and the residue was concentrated until a relative density of 1.35 (55-60 ° C) was obtained, and Radix Salviae Miltiorrhizae - Radix Notoginseng extract was obtained.

This extract was uniformly mixed with 0.34 g of borneol and 23 g of polyethylene glycol-6000. The resulting mixture was melted at 89 ° C for 100 minutes. Then the melt was introduced into the receiver of the machine for the manufacture of droplet pills, and the receiver was maintained at a temperature of 85 ° C, the liquid was dripped into methyl silicone oil with a temperature of 8 ° C. The resulting “drop pills” were taken out, oil was removed from them and then sieved through a sieve to obtain the desired preparation.

     Example 4 (preparative example)

31.12 g of Radix Salviae Miltiorrhizae and 9.21 g of Radix Notoginseng were weighed, sodium hydroxide was added in an amount of 0.5% based on the total weight of these medicinal substances. The resulting mixture was boiled in 4 times the amount of water for 1.5 hours and then in 3 times the amount of water for another 1.5 hours. After filtration, the combined filtrates were concentrated to obtain a specific gravity of 1.19-1.20 (75 ± 1 ° C). Then 88% ethanol was added in an amount sufficient to obtain an ethanol content of 66% (20 ° C). Then the mixture was kept for 10 h and the supernatant was separated. Ethanol was separated from the supernatant and the residue was concentrated until a relative density of 1.40 (55-60 ° C) was obtained, and Radix Salviae Miltiorrhizae - Radix Notoginseng extract was obtained.

This extract was uniformly mixed with 0.50 g of borneol, 90 g of mannitol, 15 g of calcium calcium edetate and 15 ml of distilled water. The resulting mixture was lyophilized and obtained from it powder for injection.

     Example 5 (preparative example)

116.35 g of Radix Salviae Miltiorrhizae and 58.21 g of Radix Notoginseng were weighed, sodium bicarbonate was added in an amount of 2.0% based on the total weight of these medicinal substances. The resulting mixture was boiled in 4 times the amount of water for 2 hours and then in 3 times the amount of water for 1.5 hours. After filtration, the combined filtrates were concentrated to obtain a specific gravity of 1.19-1.20 (75 ± 1 ° C). Then 88% ethanol was added in an amount sufficient to obtain an ethanol content of 66% (20 ° C). The mixture was then allowed to stand for 10 hours and the supernatant was separated. Ethanol was separated from the supernatant and the residue was concentrated until a relative density of 1.40 (55-60 ° C) was obtained, and Radix Salviae Miltiorrhizae - Radix Notoginseng extract was obtained.

The extract obtained was uniformly mixed with 1.80 g of Lignum Dalbergie Odoriferae oil and 40 g of microcrystalline cellulose. A 3% solution of povidone in ethanol was added to soften the mass. The resulting mass was pressed through an 18 mesh sieve to obtain granules. The granules were dried at a temperature of 60 ° C for 35 minutes, burrs were removed, and then evenly mixed with 4 g of talcum powder. The resulting mixture was encapsulated to obtain the desired preparation.

     Example 6 (preparative example)

116.35 g of Radix Salviae Miltiorrhizae and 58.21 g of Radix Notoginseng were weighed, sodium bicarbonate was added in an amount of 2.0% based on the total weight of these medicinal substances. The resulting mixture was boiled in a 4-fold amount of water for 2 hours and then in a 3-fold amount of water for 1.5 hours. After filtration, the combined filtrates were concentrated to a specific gravity of 1.19-1.20 (75 ± 1 ° C). Then 88% ethanol was added in an amount sufficient to obtain an ethanol content of 66% (20 ° C). Then the mixture was kept for 10 h and the supernatant was separated. Ethanol was separated from the supernatant, the residue was concentrated to a relative density of 1.40 (55-60 ° C), and Radix Salviae Miltiorrhizae - Radix Notoginseng extract was obtained.

The extract obtained was uniformly mixed with 0.90 g of borneol, 120 g of microcrystalline cellulose, 40 g of hydroxypropyl methylcellulose, 5 g of xylitol and 2 g of magnesium stearate. The resulting mixture was compressed to obtain tablets of the desired preparation.

     Example 7 (preparative example)

140.35 g of Radix Salviae Miltiorrhizae and 36.42 g of Radix Notoginseng were weighed, 2.5% sodium bicarbonate was added based on the total weight of these drugs. The resulting mixture was boiled in a 4-fold amount of water for 2 hours and then in a 3-fold amount of water for 1.5 hours. After filtration, the combined filtrates were concentrated to a specific gravity of 1.19-1.20 (75 ± 1 ° C). Then, 90% ethanol was added in an amount sufficient to obtain an ethanol content of 65% (20 ° C). Then the mixture was kept for 8 hours and the supernatant was separated. Ethanol was separated from the supernatant, the residue was concentrated until a relative density of 1.35 (55-60 ° C) was obtained, and Radix Salviae Miltiorrhizae - Radix Notoginseng extract was obtained.

This extract was uniformly mixed with 1.00 g of borneol and 46 g of microcrystalline cellulose. A 3% solution of povidone in ethanol was added to soften the mass. The resulting mass was pressed through an 18 mesh sieve to obtain granules. The granules were dried at a temperature of 60 ° C for 30 minutes, burrs were removed, and then evenly mixed with 4 g of talcum powder. The resulting mixture was compressed to obtain tablets of the desired preparation.

     Example 8 (example of the detection of the active component)

     1. Sample preparation

    (1) Water-soluble components of Radix Salviae Miltiorrhizae in the TCM preparation of the invention

148.4 mg of TCM dropping pills from Examples 1, 2, 3, TCM powders for injection from Example 4, TCM capsules from Example 5, oral disintegrating TCM tablets from Example 7 were weighed in. These weigheds were dissolved in 6 ml of water for 15 min. when exposed to ultrasound and then filtered through a 0.45 μm thick nylon film to obtain yellow solution samples.

    (2) Radix Notoginseng Components and Liposoluble Components in Radix Salviae Miltiorrhizae in the TCM Preparation of the Invention

1003.8 mg of TCM dropping pills from Examples 1, 2, 3, TCM powders for injection from Example 4, TCM capsules from Example 5, oral disintegrating TCM tablets from Example 7 were weighed in. These preparations were dissolved in 10 ml of 4% aqueous ammonia solution for 15 min under the influence of ultrasound and then filtered through a 0.45 μm thick nylon film. The filtrates were pretreated on an Extract-Clean C ₁₈ column (Alltech Associates, Inc., US). Samples after loading into the column were washed with 10 ml of water and then eluted with 2 ml of methanol to obtain the test sample as a yellow eluent.

    2. Sample analysis

   (1) Instruments and agents

Agilent Series-1100 Liquid Chromatography Chromatograph (Agilent); Detector G 1315A Diode Array; Automatic sample injector G 1313A; Thermostat G 1316A; Diaerator and twin pump G 1322A; HP Instrument Chromatography Workstation

Mass spectrograph Type G2445A Series 1100 LC-MSD / Trap (Bruker); ionization was carried out by electron spraying; Extract-Clean C ₁₈ column (100 mg / ml, Alltech Associates, Inc., US); acetonitrile was chromatographically pure (TEDIA), water was distilled twice, acetic acid was analytically pure.

    (2) Detection conditions

For performing HPLC, an Agilent Zorbax SB-C18 chromatography column (5 μm, 4.6 mm × 25 cm, Agilent, SN: USCL 009296) was used. Gradient elution and mass spectral determination of each sample was carried out under the following conditions:

    (a) Water-soluble components of Radix Salviae Miltiorrhizae in the TCM preparation from each example.

Elution conditions during HPLC:

Time (min) Mobile phase A (%) Mobile phase B (%) Mobile phase A: acetic acid: water = 0.01: 100
Mobile phase B: acetic acid: acetonitrile = 0.01: 100
Flow Rate: 0.5 ml / min
Temperature: 30 ° C
Detection wavelength multiple wavelength (280 nm of the specified wavelength) 0 95 0 5,0 fifteen 78.3 21.7 33 78.3 21.7 38 65.0 35.0

Conditions for MS (MS):

GHUR-MS GHUR-MS ⁿ Ionization method Negative ions Dry gas flow rate (L / min) 10 10 Nebulizer Pressure (psi ² ) 60 60 Temperature (° C) 350 350 Capillary voltage (V) 3500 3500 Scan Area (m / z) 100-1200 100-800 Amplitude (eV) 1.5-3.0

    (b) Radix Notoginseng components in the TCM preparation in each example.

HPLC Elution Conditions:

Time (min) Mobile phase A (%) Mobile phase B (%) Mobile phase A: acetic acid: water = 0.01: 100
Mobile phase B: acetic acid: acetonitrile = 0.01: 100
Flow Rate: 0.8 ml / min
Temperature: 30 ° C
Detection wavelength multiple wavelength (203 nm of the specified wavelength) 0 80 twenty fifteen 65 35 25 65 35 40 87 43 fifty 54 46 65 42 58 75 25 75

    Conditions for conducting MS:

GHUR-MS GHUR-MS ⁿ Ionization method Negative ions Dry gas flow rate (L / min) 10 10 Nebulizer Pressure (psi ² ) 60 60 Temperature (° C) 350 350 Capillary voltage (V) 3500 3500 Scan Area (m / z) 400-1500 400-1200 Amplitude (eV) 1.2-1.5

     3. Analysis of the results and identification of peaks

The components were identified in two aspects: (1) using control samples; (2) using UV absorption and ion fragment information based on MS ⁿ (MS ⁿ ) data in combination with literature data.

     4. Identification Results

    (1) The water-soluble components of Radix Salviae Miltiorrhizae in the Radix Salviae Miltiorrhizae preparation for each example of this invention (see Tables 1 and 2 and Figures 2 and 3).

Table 1 GHUR-MS data and identification results Peak No. Retention time The peak of the quasimolecular ion m / z [MH] ^- Identity Wavelength max. absorption, λ _max one 12.73 197 Danshensu 280 2 19.69 137 Protocatechialdehyde 231, 280, 310 3 22,99 537 Isolospermic Acid A 327 four 23.83 537 Isolospermic Acid B 327 5 24.89 417 Salvianolic Acid D 247, 321 6 26.70 717 Salvianolic Acid E 330 7 28.51 359 Rosmarinic acid 329 8 31.93 717 Salvianolic Acid B 254, 286, 309 9 34.86 339 Salvianolic Acid G 395 10 44.64 493 Salvianolic Acid A 288

table 2 Data GHUR-MS ⁿ Peak No. Identity Ion fragment 3 Isolospermic Acid A Second (537): 493 [M-H-CO ₂ ] ^- , 295 [M-CO ₂ -RH ₂ O] ^- , Third (295): 159, 109 four Isolospermic Acid B Second (537): 493 [M-H-CO ₂ ] ^- , 295 [M-CO ₂ -RH ₂ O] ^- , Third (295): 159, 109 5 Salvianolic Acid D Second (417): 175 [M-CO ₂ -RH ₂ O] ^- , 373 [MH-CO ₂ ] ^- , Third (175): 147, 157, 133 6 Salvianolic Acid E Second (717): 519 [MRH ₂ O] ^- , 321 [M-2R-2H ₂ O] ^- ,
Third (519): 321 [MRH ₂ O] ^- , 339 [MR] ^- ,
Third (321): 279, 293, 249,223,185 7 Rosmarinic acid Second (359): 161 [MRH ₂ O] ^- , 179 [MR] -, 195 8 Salvianolic Acid B Second (717): 519 [MRH ₂ O] ^- , 321 [M-2R-2H ₂ O] ^- ,
Third (519): 321 [MRH ₂ O] ^- , 339 [MR] ^- ,
Fourth (321): 279, 293, 249, 233, 185 9 Salvianolic Acid G Second (339): 321 [MHH ₂ O] ^- , 295 [MH-CO ₂ ] ^- , Third (295): 279, 267
Fourth (279): 251 10 Salvianolic Acid A Second (493): 295 [MRH ₂ O] ^- ,
Third (295): 159, 109

From the results of MS ^n, it can be seen that the second and third peaks have very similar lithospermic acid structures. However, in the case of UV absorption, these peaks are significantly different from lithospermic acid. Lithospermic acid is characterized by a relatively large absorption at a wavelength of about 253 nm due to the phenylcumaran chain, and the second and third peaks do not have this property. Both of these peaks have UV absorption very similar to that of salvianolic acid E, which indicates that the two compounds corresponding to these two peaks probably have the same backbone as Salvianolic acid E, namely the carboxyldiphenylethylene backbone. Therefore, we can conclude that they have structures, such as the structure of isolitospermic acids A and B, shown in the above structural formulas for the components. These two structures have never been described and are therefore referred to as isolospermic acids A and B.

    (2) Liposoluble components of Radix Salviae Miltiorrhizae in the TCM preparation of the invention (see Table 3 and Figures 4 and 5).

Table 3 GHUR-MS data and identification results Peak No. Retention time The peak of the quasimolecular ion m / z ^is Identity one 24.36 277 [M + H] ⁺ , 575 [2M + Na] ⁺ Tanshinon I 2 34.85 295 [M + H] ⁺ , 611 [2M + Na] ⁺ Tanshinon IIA

    (3) Components of Radix Notoginseng in the Radix Salviae Miltiorrhizae drip pills of the present invention (see Tables 4 and 5 and Figure 6).

Table 4 GHUR-MS data and identification results. Peak No. Retention time The peak of the quasimolecular ion m / z [MH] ^- Identity one 11.27 931 Notoginsenoside R ₁ 2 12.38 945 Ginsenoside Re 2 12.53 799 Ginsenoside Rg ₁ 3 20.81 1107 Ginsenoside Rb ₁ four 21.25 769 Notoginsenoside R ₂ 5 22.53 769 Notoginsenoside R ₂ -iso 6 22.85 783 Ginsenoside Rg ₂ 7 23.77 637 Ginsenoside Rh ₁ 8 25.00 637 Ginsenoside Rh ₁ iso (F ₁ ) 9 30.05 945 Ginsenoside Rd 10 34.81 945 Ginsenoside Rd iso eleven 40.00 781 Ginsenoside Rf-H ₂ O 12 41.57 751 Notoginsenoside R ₂ -H ₂ O 13 43.72 751 Notoginsenoside R ₂ -H ₂ O fourteen 44.89 765 Ginsenoside Rg ₆ / F ₄ fifteen 46.43 619 Ginsenoside Rk ₃ / Rh ₄ (Rk ₃ ) 16 48.68 619 Ginsenoside Rk ₃ / Rh ₄ (Pk ₄ ) 17 54.97 783 Ginsenoside 20 (R) Rg ₃ eighteen 56.48 783 Ginsenoside 20 (S) Rg ₃ 19 68.35 765 Ginsenoside Rk ₁ / Rg ₅ (Rk ₁ ) twenty 69.53 765 Ginsenoside Rk ₁ / Rg ₅ (Rg ₅ )

Table 5 Data GHUR-MS ⁿ Retention time Identity The peak of the quasimolecular ion m / z ^is 11.27 Notoginsenoside R ₁ 799 [MH-Xyl] ^- ; 637 [MH-Xyl-Glcp; 475 [M-H-Xyl-2Glc] ^- 12.38 Ginsenoside Re 799 [MH-Rham] ^- ; 783 [M-H-Glc] ^- ; 637 [MH-Rham-Glc] ^- ; 475 [MH-Rham-2Glc] ^- 12.53 Ginsenoside Rg ₁ 637 [M-H-Glc] ^- ; 475 [MH-2Glc] ^- 20.81 Ginsenoside Rb ₁ 945 [MH-Glc] ^- ; 783 [MH-2Glc] ^- ; 624 [MH-3Glc] ^- ; 459 [M-H-4Glc] ^- 21.25 Notoginsenoside R ₂ 637 [MH-Xyl] ^- ; 475 [M-H-Xyl-Glc] ^- 22.53 Notoginsenoside R ₂ -iso 637 [MH-Xyl] ^- ; 475 [MH-Xyl-Glc] ^- 22.85 Ginsenoside Rg ₂ 637 [MH-Rham] ^- ; 475 [M-H-Rham-Glc] ^- 23.77 Ginsenoside Rh ₁ 475 [M-H-Glc] ^- 25.00 Ginsenoside Rh ₁ iso (F ₁ ) 475 [MH-Glc] ^- 30.05 Ginsenoside Rd 783 [M-H-Glc] ^- ; 621 [MH-2Glc] ^- ; 459 [MH-3Glc] ^- 34.81 Ginsenoside Rd iso 783 [M-H-Glc] ^- ; 621 [MH-2Glc] ^- ; 459 [MH-3Glc] ^- 40.00 Ginsenoside Rf-H ₂ O 619 [M-H-Glc] ^- ; 457 [MH-2Glc] ^- 41.57 Notoginsenoside R ₂ -H ₂ O 619 [MH-Xyl] ^- 43.72 Notoginsenoside R ₂ -H ₂ O 619 [MH-Xyl] ^- 44.89 Ginsenoside Rg ₆ / F ₄ 619 [MH-Rham] ^- ; 457 [M-H-Rham-Glc] ^- 54.97 Ginsenoside 20 (R) Rg ₃ 621 [MH-Glc] ^- ; 459 [MH-2Glc] ^- 56.48 Ginsenoside 20 (S) Rg ₃ 621 [M-H-Glc] ^- ; 459 [MH-2Glc] ^- 68.35 Ginsenoside Rk ₁ / Rg ₅ (Rk ₁ ) 603 [M-H-Glc] ^- ; 441 [MH-2Glc] ^- 69.53 Ginsenoside Rk ₁ / Rg ₅ (Rg ₅ ) 603 [M-H-Glc] ^- ; 441 [MH-2Glc] ^-

Based on the above studies, an extraction method and an analysis method for the TCM preparation according to the invention were developed, which include:

    (1) a solid-phase method for the extraction of liposoluble components of Radix Salviae Miltiorrhizae and components of Notoginsenoside (notoginsenoside) from drop pills based on Radix Salviae Miltiorrhizae;

    (2) HPLC-MS analysis method for each sample.

Altogether, 12 Radix Salviae Miltiorrhizae components and 21 Radix Notoginseng saponin components were identified. Among them, when compared with control samples, 4 water-soluble components of Radix Salviae Miltiorrhizae, 2 lip-soluble components of Radix Salviae Miltiorrhizae, and 9 components of saponin were identified, and other compounds were mainly identified on the basis of MS ^- data and comparisons with published data

     Example 9 (Example of detection of fingerprint atlas for components of Radix Salviae Miltiorrhizae in a TCM preparation)

     1. Devices and agents

Instruments: Agilent 1100 Liquid Chromatograph, containing a four-channel pump, an on-line deaerating system, an automatic sample injector, a DAD detector, a column temperature controller, a Chemstation workstation; electronic balance (1/10 ^-4 g) BS 210S (Beijing Sartorius Company), electronic balance (1/10 ^-4 g or 1/10 ^-5 g) AE240 (Mettler-Toledo Corporation, Shanghai), centrifuge LD4-2 ( 4000 rpm) (Beijing Medical Centrifuge Factory), water bath with a digital thermostat (Tianging Changfeng Corporation), rotary evaporator RE-52AA (Shanghai Yarong Biochemical Instrumentation Factory), vacuum pump with circulating water SHE- (III) (Gongyi Yingyuyuhua Instrumentation Factory), KQ-250B ultrasonic cleaner (Kunshan Ultrasonic Instrumentation Corporation), HENGAO Tand D filter (HENGAO Tand D), synthetic fiber membrane filter (0.45 μm openings) (Shanghai Xingya Purifying Materials Factory).

Agents: acetonitrile (chromatographically pure, Merck Company, US), phosphoric acid (superior quality), pure Wahaha water.

     2. Obtaining the test sample

10 pills of TCM preparation from each batch in Example 1 were weighed and then placed in a 10 ml measuring flask. Distilled water was added in an amount sufficient to dissolve the pills by shaking under the influence of ultrasound for 15 minutes. Then, distilled water was added again until a volume of 10 ml was reached. The resulting solution was centrifuged or filtered to obtain a sample of the solution.

     3. Terms of GHUR

Agilent ZoRBAx SB-C18 chromatography column (4.6 × 250 mm, 5 μm; mobile phase: mobile phase A: 0.02% aqueous phosphoric acid; mobile phase B: 80% acetonitrile - 0.02% aqueous phosphoric acid ; flow rate: 1,000 ml / min; detection wavelength 280 nm; column temperature: 30 ° C; sample volume introduced: 10 μl.

Table 6 Mobile Phase Elution Gradient Retention time Mobile phase A, (V / V) Mobile phase B (V / V) 0 min 90% 10% 8 min 78% 22% 15 minutes 74% 26% 55 min 48% 52%

     4. The results of the detection (see Table 7)

Table 7 The results of the detection of the components of Radix Salviae Miltiorrhizae in 200 batches of drop pills of the TCM preparation Peak No. Average retention time RSD% of retention time Average peak area RSD% of peak area Ratio of individual peak area to total peak area The ratio of the interval of values of the area of an individual peak to the total area of peaks one 6.04 0.31 1627.92 5.91 20.80% 19.6% -22.0% 2 9.90 0.25 2575.54 13.53 32.90% 28.5% -37.4% 3 16.89 0.61 366.89 10.92 4.69% 4.2% -5.2% four 17.84 0.70 381.40 13.81 4.87% 4.2% -5.5% 5 20.31 0.96 186.08 12.04 2.38% 2.1% -2.7% 6 23.74 0.76 555.35 10.48 7.09% 6.4% -7.8% 7 27.73 0.50 281.91 18.08 3.60% 3.0% -4.3% 8 31.02 1.18 1852.33 14.84 23.66% 20.2% -27.2% Note:
Peak 1 corresponds to Danshensu; peak 2 corresponds to protocatechialdehyde; peak 3 corresponds to isolispermic acid A; peak 4 corresponds to isolispermic acid B; peak 5 corresponds to salvianolic acid D; peak 6 corresponds to rosmarinic acid; peak 7 corresponds to salvianolic acid B and peak 8 corresponds to salvianolic acid A (see Figure 1).

Table 7 shows the relative positions and sizes of the areas (retention time and peak area) of 8 peaks, and for 3 peaks the ratio of the area of an individual peak to the total area of peaks is more than 10% and for all 8 peaks the ratio of the area of an individual peak the total peak area is more than 2%.

Claims (11)

1. A drug for the treatment of cardiovascular and cerebrovascular diseases, containing isolospermic acids A and B, which are characterized in the mass spectra by the peak of the quasimolecular ion with m / z 537 [M-H] ^- , the second ionic fragment with m / z 493 [M- H-CO ₂ ] ^- and 295 [M-CO ₂ -RH ₂ O] ^- and the third ionic fragment with m / z 159 and 109 at a maximum absorption wavelength of 327 nm, while mass spectroscopy is carried out as follows:
(1) HPLC-MS is carried out through the negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage 3500 V and scan range m / z 100-1200 and
(2) HPLC-MS is carried out by ⁿ negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage: 3500 V and scanning range m / z 100-800; and the amplitude of the fragments is 1.5-3.0 V. 2. The drug according to claim 1, characterized in that it contains components characterized by a peak of a quasimolecular ion with m / z 417, 717, 359, 717, 339 and 493 [M-H] ^, respectively, and the component with a mass of 417 [ M-H] ^- contains a second ionic fragment with m / z 175 [M-CO ₂ -P-H ₂ O] ^- and 373 [M-H-CO ₂ ] ^- and a third ionic fragment with m / z 147, 157 and 133;
component with a mass of 717 [M-H] ^- contains a second ionic fragment with m / z 519 [MRH ₂ O] ^- and 321 [MRH ₂ O] ^- , a third ionic fragment with m / z 339 [M-H] ^- and a third an ionic fragment with m / z 279, 293, 249, 223 and 185;
component with a mass of 359 [M-H] ^- contains a second ionic fragment with m / z 161 [MRH ₂ O] ^- , 179 [MR] ^- and 195;
component with a mass of 717 [M-H] ^- contains a second ionic fragment with m / z 519 [MRH ₂ O] ^- , 321 [M-2R-2H ₂ O] ^- ; a third ionic fragment with m / z 321 [M-RH ₂ O] ^- and 339 [MR] ^- and a fourth ionic fragment with m / z 279, 293, 249, 223 and 185;
component with a mass of 339 [M-H] ^- contains a second ionic fragment with m / z 321 [MRH ₂ O] ^- and 295 [M-H-CO ₂ ] ^- ; the third ionic fragment with m / z 279 and 267 and the fourth ionic fragment with m / z 251 and
component with mass 493 [M-H] ^- contains a second ionic fragment with m / z 295 [MRH ₂ O] ^- and a third ionic fragment with m / z 159 and 109; moreover, mass spectroscopy is carried out as follows:
(1) HPLC-MS is carried out through the negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage 3500 V and scan range m / z 100-1200 and
(2) HPLC-MS is carried out by ⁿ negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage: 3500 V and scanning range m / z 100-800; and the amplitude of the fragments is 1.5-3.0 V. 3. The drug according to claim 1, characterized in that it contains components characterized by a peak of a quasimolecular ion with m / z 931, 945, 799, 1107, 769, 769, 783, 637, 637, 945, 945, 781, 751 , 751, 765, 619, 619, 783, 783, 765 and 765 [M-H] ^- respectively, and
component with a mass of 931 [M-H] ^- contains an ionic fragment with m / z 799 [M-H-Xyl] ^- , 637 [MH-Xyl-Glc] ^- and 475 [MH-Xyl-2Glc] ^- ;
component with a mass of 945 [M-H] ^- contains an ionic fragment with m / z 799 [M-H-Rham] ^- , 783 [MH-Glc] ^- , 637 [MH-Rham-Glc] ^- and 475 [MH-Rham -2Glc] ^- ; component with a mass of 799 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Glc] ^- and 475 [MH-2Glc] ^- ;
component with a mass of 1107 [M-H] ^- contains an ionic fragment with m / z 945 [M-H-Glc] ^- , 783 [MH-2Glc] ^- , 621 [MH-3Glc] ^- and 459 [MH-4Glc] ^- ; component with a mass of 769 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Xyl] ^- and 475 [MH-Xyl-Glc] ^- ;
component with a mass of 769 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Xyl] and 475 [MH-Xyl-Glc] ^- ;
component with a mass of 783 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Rham] ^- and 475 [MH-Rham-Glc] ^- ;
component with a mass of 637 [M-H] ^- contains an ionic fragment with m / z 475 [M-H-Glc] ^- ;
component with a mass of 637 [M-H] ^- contains an ionic fragment with m / z 475 [M-H-Glc] ^- ;
component with a mass of 945 [M-H] ^- contains an ionic fragment with m / z 783 [M-H-Glc] ^- , 621 [MH-2Glc] ^- , 459 [MH-3Glc] ^- ;
component with a mass of 945 [M-H] ^- contains an ionic fragment with m / z 783 [M-H-Glc] ^- , 621 [MH-2Glc] ^- , 459 [MH-3Glc] ^- ;
component with a mass of 781 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Glc] ^- and 457 [MH-2Glc] ^- ;
component with a mass of 751 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Xyl] ^- ;
component with a mass of 751 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Xyl] ^- ;
component with a mass of 765 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Rham] ^- and 457 [MH-Rham-Glc] ^- ;
component with a mass of 783 [M-H] ^- contains an ionic fragment with m / z 621 [M-H-Glc] ^- and 459 [MH-2Glc] ^- ;
component with a mass of 783 [M-H] ^- contains an ionic fragment with m / z 621 [M-H-Glc] ^- and 459 [MH-2Glc] ^- ;
component with a mass of 765 [M-H] ^- contains an ionic fragment with m / z 603 [M-H-Glc] ^- and 441 [MH-2Glc] ^- ;
component with a mass of 765 [M-H] ^- contains an ionic fragment with m / z 603 [M-H-Glc] ^- and 441 [MH-2Glc] ^- ;
while mass spectroscopy is carried out as follows:
(1) HPLC-MS is carried out through the negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage 3500 In and scan range m / z 400-1500 and
(2) HPLC-MS is carried out by ⁿ negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage: 3500 V and scanning range m / z 400-1200; and the amplitude of the fragments is 1.2-1.5 V. 4. The drug according to claim 1, characterized in that it contains components characterized by a peak of a quasimolecular ion with m / z 417, 717, 359, 717, 339 and 493 [M-H] ^, respectively, with the component weighing 417 [ M-H] ^- contains a second ionic fragment with m / z 175 [M-CO ₂ -RH ₂ O] ^- and 373 [M-H-CO ₂ ] ^- and a third ionic fragment with m / z 147, 157 and 133;
component with a mass of 717 [M-H] ^- contains a second ionic fragment with m / z 519 [MRH ₂ O] ^- and 321 [M-2R-2H ₂ O] ^- , a third ionic fragment with m / z 321 [MRH ₂ O ] ^- and 339 [MR] ^- and the fourth ionic fragment with m / z 279, 293, 249, 223 and 185;
component with a mass of 359 [M-H] ^- contains a second ionic fragment with m / z 161 [MRH ₂ O] ^- 179 [MR] ^- and 195;
component with a mass of 717 [M-H] ^- contains a second ionic fragment with m / z 519 [MRH ₂ O] ^- and 321 [M-2P-2H ₂ O] ^- , a third ionic fragment with m / z 321 [MRH ₂ O ] ^- and 339 [MR] ^- and the fourth ionic fragment with m / z 279, 293, 249, 223 and 185;
component with a mass of 339 [M-H] ^- contains a second ionic fragment with m / z 321 [MRH ₂ O] ^- and 295 [MR-CO ₂ ] ^- , a third ionic fragment with m / z 279 and 267 and a fourth ionic fragment with m / z 251; and
component with mass 493 [M-H] ^- contains a second ionic fragment with m / z 295 [MRH ₂ O] ^- and a third ionic fragment with m / z 159 and 109; moreover, mass spectroscopy is as follows:
(1) HPLC-MS is carried out through the negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage 3500 V and scan range m / z 100-1200 and
(2) GHUR-MSP is performed by detecting negative ions under the following conditions: dry gas flow rate 10 l / min, nebulizer pressure 60 psi (413.68 kPa), dry gas temperature 350 ° C, capillary voltage 3500 V and a scanning range of m / z 100-800; and the amplitude of the fragments is 1.5-3.0 V.
and additionally contains components characterized in the mass spectra by the peak of the quasimolecular ion with m / z 931, 945, 799, 1107, 769, 769, 783, 637, 637, 945, 945, 783, 751, 751, 765, 783, 783 , 765 and 765 [M-H] ^- , while
component with a mass of 931 [M-H] ^- contains an ionic fragment with m / z 799 [M-H-Xyl] ^- , 637 [MH-Xyl-Glc] ^- and 475 [MH-Xyl-2Glc] ^- ;
component with a mass of 945 [M-H] ^- contains an ionic fragment with m / z 799 [M-H-Rham] ^- , 783 [MH-Glc] ^- , 637 [MH-Rham-Glc] ^- and 475 [MH-Rham -2Glc] ^- ;
component with a mass of 799 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Glc] ^- and 475 [MH-2Glc] ^- ;
component with a mass of 1107 [M-H] ^- contains an ionic fragment with m / z 945 [M-H-Glc] ^- , 783 [MH-2Glc] ^- , 621 [MH-3Glc] ^- and 459 [MH-4Glc] ^- ; component with a mass of 769 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Xyl] ^- and 475 [MH-Xyl-Glc] ^- ;
component with a mass of 769 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Xyl] ^- and 475 [MH-Xyl-Glc] ^- ;
component with a mass of 783 [M-H] ^- contains an ionic fragment with m / z 637 [M-H-Rham] ^- and 475 [MH-Rham-Glc] ^- ;
component with a mass of 637 [M-H] ^- contains an ionic fragment with m / z 475 [M-H-Glc] ^- ;
component with a mass of 637 [M-H] ^- contains an ionic fragment with m / z 475 [M-H-Glc] ^- ;
component with a mass of 945 [M-H] ^- contains an ionic fragment with m / z 783 [M-H-Glc] ^- , 621 [MH-2Glc] ^- , 459 [MH-3Glc] ^- ;
component with a mass of 945 [M-H] ^- contains an ionic fragment with m / z 783 [M-H-Glc] ^- , 621 [MH-2Glc] ^- , 459 [MH-3Glc] ^- ;
component with a mass of 781 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Glc] ^- and 457 [MH-2Glc] ^- ;
component with a mass of 751 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Xyl] ^- ;
component with a mass of 751 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Xyl] ^- ;
component with a mass of 765 [M-H] ^- contains an ionic fragment with m / z 619 [M-H-Rham] ^- and 457 [MH-Rham-Glc] ^- ;
component with a mass of 783 [M-H] ^- contains an ionic fragment with m / z 621 [M-H-Glc] ^- and 459 [MH-2Glc] ^- ;
component with a mass of 783 [M-H] ^- contains an ionic fragment with m / z 621 [M-H-Glc] ^- and 459 [MH-2Glc] ^- ;
component with a mass of 765 [M-H] ^- contains an ionic fragment with m / z 603 [M-H-Glc] ^- and 441 [MH-2Glc] ^- ;
component with a mass of 765 [M-H] ^- contains an ionic fragment with m / z 603 [M-H-Glc] ^- and 441 [MH-2Glc] ^- ;
while mass spectroscopy is carried out as follows:
(1) HPLC-MS is carried out through the negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage 3500 In and scan range m / z 400-1500 and
(2) HPLC-MS is carried out by ⁿ negative ion detection under following conditions: dry gas flow rate of 10 l / min, the nebulizer pressure 60 lb / ⁱⁿ² (413.68 kPa), dry gas temperature 350 ° C, capillary voltage: 3500 V and scanning range m / z 400-1200; and the amplitude of the fragments is 1.2-1.5 V. 5. The drug according to claim 1, characterized in that it contains salvianolic acid D, salvianolic acid E, rosmarinic acid, salvianolic acid B, salvianolic acid G, salvianolic acid A, Danshensu, protocatechialdehyde, isolite spermic acid A, isolospermic acid A, isolospermic acid A, tanshinone I, tanshinone IIA, Notoginsenoside R _1, Ginsenoside Re, Ginsenoside Rg _1, ginsenoside Rb _1, Notoginsenoside R _2, R ₂ Notoginsenoside iso, ginsenoside Rg _2, ginsenoside Rh _1, Rh Ginsenoside -iso _1, Ginsenoside Rd, Ginsenoside Rd iso , ginsenoside Rf-H ₂ O, notoginsenoside R ₂ - H ₂ O, ginsenoside Rg ₆ or F ₄ , ginsenoside 20 (R) -Rg ₃ , ginsenoside
20 (S) -Rg ₃ , ginsenoside Rk ₁ , ginsenoside Rg ₅ , ginsenoside Rk ₃ and ginsenoside Rh ₄ . 6. The drug according to claim 1, characterized in that it is characterized by the following physical and chemical parameters:
there are 8 peaks in the HPLC spectrum, in which the ratio of the area of an individual peak to the total peak area is more than 2%; the average retention time for these 8 peaks is 6.04, 9.90, 16.89, 17.84, 20.31, 23.74, 27.73 and 31.02, respectively; RSD% of the retention time is 0.31, 0.25, 0.61, 0.70, 0.96, 0.76, 0.50 and 1.18, respectively; the average peak area is 1627.92, 2575.54, 366.89, 381.40, 186.08, 555.35, 281.91 and 1852.33, respectively; RSD% of the peak area is 5.91, 13.53, 10.92, 13.81, 12.04, 10.48, 18.08 and 14.84, respectively; and the ratio of the area of an individual peak to the total peak area is 19.6-22.0%, 28.5-37.4%, 4.2-5.2%, 4.2-5.5%, 2.1- 2.7%, 6.4-7.8%, 3.0-4.3% and 20.2-27.2%, respectively;
moreover, the above physical and chemical parameters are determined under the following conditions:
(1) high performance liquid chromatography:
filler: octadecylsilylsilica gel, flow rate 1,000 ml / min; detection wavelength of 280 nm and
(2) elution:
mobile phase A: 0.02% aqueous phosphoric acid solution; mobile phase B: 80% acetonitrile - 0.02% aqueous phosphoric acid solution; elution gradient: mobile phase A evenly changes from 90 to 78% and mobile phase B evenly changes from 10 to 22% for 0-8 min, mobile phase A changes from 78 to 74% and mobile phase B varies from 22 to 26% within 8-15 minutes and the mobile phase A changes from 74 to 48% and the mobile phase B changes from 26 to 52% within 15-55 minutes;
in this case, a sample of the solution is prepared and analyzed during the following stages: accurate weighing of 10 pills of a traditional Chinese drug and placing them in a measuring vessel with a volume of 10 ml; adding distilled water in an amount sufficient to dissolve the drug with shaking and exposure to ultrasound for 15 minutes; adding distilled water to reach a volume of 10 ml; centrifuging or filtering the resulting solution to obtain a sample of the solution; introducing exactly 10 μl of a sample of the solution into the HPLC system and analyzing the sample of the solution by HPLC to obtain HPLC spectra. 7. The drug according to claim 6, characterized in that 8 peaks with an average retention time of 6.04, 9.90, 16.89, 17.84, 20.31, 23.74, 27.73 and 31, 02 respectively correspond to Danshensu, protocatechialdehyde, isolispermic acid A, isolispermic acid B, salvianolic acid D, rosmarinic acid, salvianolic acid B and salvianolic acid A, respectively. 8. A method of manufacturing a medicinal product for the treatment of cardiovascular and cerebrovascular diseases according to any one of claims 1 to 7, comprising the steps of:
weighing Radix Salviae Miltiorrhizae and Radix Notoginseng; adding sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate or a mixture thereof in an amount of 0.5-4% based on the total weight of these medicinal substances to obtain a mixture;
boiling the mixture in 3-6-fold amount of water 2-4 times; filtering the mixture and concentrating the combined filtrates; adding ethanol with a high concentration (more than 70%) in an amount sufficient to obtain an ethanol content of 65-70%; sedimentation of the mixture and separation of the supernatant; separating ethanol from the supernatant and concentrating the residue until its relative density becomes 1.20-1.50 to obtain Radix Salviae Miltiorrhizae-Radix Notoginseng 'extract, mixing the resulting extract with borneol or Lignum Dalbergie Odoriferae oil (odorous ) and adding excipient to obtain the drug. 9. The method of claim 8, wherein said excipient is a substance selected from starch, dextrin, lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose, lactitol, glucose, glycine, mannitol, methylated starch sodium, cross-linked sodium carboxymethyl cellulose, polyvinylpyrrolidone, as such, either in water or a mixture of more than one of these, and the drug is obtained in the form of a dosage form - tablets, tablets with prolonged action, pills, granules, powder for injection, capsule, microgranules or oral disintegrant. 10. The method according to claim 9, characterized in that this preparation is in the form of drip pills. 11. The method according to claim 10, characterized in that it comprises the steps of: weighing Radix Salviae Miltiorrhizae and Radix Notoginseng ', adding sodium bicarbonate in an amount of 1.4-1.9% based on the total weight of the medicinal substances to obtain a mixture;
boiling the mixture in a 4-5-fold amount of water for 2-3 hours and then in a 3-4-fold amount of water for 1-2 hours; filtering the mixture and concentrating the combined filtrates until a specific gravity of 1.16-1.20 is reached; adding ethanol with a high concentration (above 70%) in an amount sufficient to obtain an ethanol content of 65-70%; keeping the mixture for 8-12 hours and separating the supernatant;
separation of ethanol from the supernatant and concentration of the residue to obtain a relative density of 1.32-1.40, with the formation of the extract of Radix Salviae Miltiorrhizae - Radix Notoginseng; mixing said extract with borneol or Lignum Dalbergie Odoriferae oil and polyethylene glycol-6000 to obtain a uniform mixture;
heating the mixture until it melts;
introducing the melt dropwise into the cooler - liquid paraffin or methyl silicone oil using the device;
taking out the obtained pills and removing oil from them and
sifting these pills to obtain the desired drug.

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